Amyloid β-Protein Assembly: Differential Effects of the Protective A2T Mutation and Recessive A2V Familial Alzheimer’s Disease Mutation

Abstract

Oligomeric states of the amyloid β-protein (Aβ) appear to be causally related to Alzheimer’s disease (AD). Recently, two familial mutations in the amyloid precursor protein gene have been described, both resulting in amino acid substitutions at Ala2 (A2) within Aβ. An A2V mutation causes autosomal recessive early onset AD. Interestingly, heterozygotes enjoy some protection against development of the disease. An A2T substitution protects against AD and age-related cognitive decline in non-AD patients. Here, we use ion mobility-mass spectrometry (IM-MS) to examine the effects of these mutations on Aβ assembly. These studies reveal different assembly pathways for early oligomer formation for each peptide. A2T Aβ42 formed dimers, tetramers, and hexamers, but dodecamer formation was inhibited. In contrast, no significant effects on Aβ40 assembly were observed. A2V Aβ42 also formed dimers, tetramers, and hexamers, but no dodecamers. However, A2V Aβ42 formed trimers, unlike A2T or wild type (wt) Aβ42. In addition, the A2V substitution caused Aβ40 to oligomerize similar to wt Aβ42, as evidenced by the formation of dimers, tetramers, hexamers, and dodecamers. In contrast, wt Aβ40 formed only dimers and tetramers. These results provide a basis for understanding how these two mutations lead to, or protect against, AD. They also suggest that the Aβ N-terminus, in addition to the oft discussed central hydrophobic cluster and C-terminus, can play a key role in controlling disease susceptibility.

The Solution Assembly of Biological Molecules Using Ion Mobility Methods: From Amino Acids to Amyloid β-Protein

“…For example, in a recent newspaper (June 29, 2016) it was reported that the iconic women’s basketball coach Pat Summit had died at age 64 from early onset Alzheimer’s disease. At UCSB, we have initiated studies on many of the mutants listed in Scheme I (67,68) but space limitation doesn’t let a detailed discussion be made of the results. What we have found so far, however, is that every mutant has profound effects on the assembly of both Aβ40 and Aβ42 leading to very different oligomer distributions and structures.…”

Comparison of Efficacy of Preventive and Therapeutic Vaccines Targeting the N Terminus of β-Amyloid in an Animal Model of Alzheimer’s Disease

“…[3][4][5] Support for the amyloid cascade hypothesis was spurred by the identification of mutations in amyloid precursor protein (APP) that are associated with familial AD [6][7][8] or protection against amyloid pathology and age-related Alzheimer's disease. [9][10][11] In addition, it was discovered that overexpression of APP due to trisomy 21 in Downs disease was associated with a high incidence of AD in these individuals. [12][13][14] Today it is clear that the pathological tau also plays a vital role in the development of AD pathology and progression of this disease, 15 correlating better with the degree of dementia than Ab plaques.…”

Differential effect of amyloid beta peptides on mitochondrial axonal trafficking depends on their state of aggregation and binding to the plasma membrane

“…Finally, our data demonstrate that Icelandic Aβ peptide with protective A673T mutation affects axonal trafficking of mitochondria and increases the number of stationary organelles similar to other Aβ peptides. This variant is associated with minimal amyloid deposition and significantly reduced amyloid production (Benilova et al, 2014; Maloney et al, 2014; Zheng et al, 2015). Therefore, these properties together with its significantly reduced binding to neuronal plasma membrane could account for the lack of pronounced pathological effect on mitochondrial trafficking since this peptide could be cleared from the brain prior to imparting mitochondrial dysfunction.…”